Using the LASSI-L to Detect Robust Interference Effects in Premanifest Huntington Disease.

BACKGROUND: Diagnosis of manifest Huntington disease (HD) is based primarily on motor symptoms, but premanifest HD (preHD) is often associated with subtle cognitive decline. The Loewenstein-Acevedo Scales for Semantic Interference and Learning (LASSI-L) is a validated verbal learning test that can be used to detect early cognitive decline. OBJECTIVE: To determine the utility of the LASSI-L for detecting early cognitive decline in individuals with preHD and to compare the results of the LASSI-L with those of commonly used neuropsychological tests in HD. METHOD: We administered the LASSI-L to 13 individuals with preHD and 13 healthy controls matched for age, sex, and education as part of a longitudinal study of disease progression. For comparison purposes, we administered the Mini-Mental State Examination; Stroop Color and Word Test; Symbol Digit Modalities Test; Trail-Making Test, Parts A and B; and category fluency (animals) task. RESULTS: Five of the seven sections on the LASSI-L captured group differences: Proactive Semantic Interference (PSI; P < 0.001), Failure to Recover From PSI ( P = 0.038), Retroactive Semantic Interference (RSI; P = 0.013), Delayed Recall ( P < 0.001), and B1 Cued Recall Intrusions ( P = 0.036). Using a false discovery rate of <0.05, PSI, RSI, and Delayed Recall remained significant. CONCLUSION: The LASSI-L is a sensitive instrument for detecting early interference effects in individuals with preHD that outperforms commonly used neuropsychological tests. The LASSI-L could be a useful addition to clinical and research protocols involving individuals with preHD.

A Multi-center Genome-wide Association Study of Cervical Dystonia.

BACKGROUND: Several monogenic causes for isolated dystonia have been identified, but they collectively account for only a small proportion of cases. Two genome-wide association studies have reported a few potential dystonia risk loci; but conclusions have been limited by small sample sizes, partial coverage of genetic variants, or poor reproducibility. OBJECTIVE: To identify robust genetic variants and loci in a large multicenter cervical dystonia cohort using a genome-wide approach. METHODS: We performed a genome-wide association study using cervical dystonia samples from the Dystonia Coalition. Logistic and linear regressions, including age, sex, and population structure as covariates, were employed to assess variant- and gene-based genetic associations with disease status and age at onset. We also performed a replication study for an identified genome-wide significant signal. RESULTS: After quality control, 919 cervical dystonia patients compared with 1491 controls of European ancestry were included in the analyses. We identified one genome-wide significant variant (rs2219975, chromosome 3, upstream of COL8A1, P-value 3.04 × 10-8 ). The association was not replicated in a newly genotyped sample of 473 cervical dystonia cases and 481 controls. Gene-based analysis identified DENND1A to be significantly associated with cervical dystonia (P-value 1.23 × 10-6 ). One low-frequency variant was associated with lower age-at-onset (16.4 ± 2.9 years, P-value = 3.07 × 10-8 , minor allele frequency = 0.01), located within the GABBR2 gene on chromosome 9 (rs147331823). CONCLUSION: The genetic underpinnings of cervical dystonia are complex and likely consist of multiple distinct variants of small effect sizes. Larger sample sizes may be needed to provide sufficient statistical power to address the presumably multi-genic etiology of cervical dystonia. © 2021 International Parkinson and Movement Disorder Society.

Validation of secondary data sources to identify Parkinson disease against clinical diagnostic criteria.

Parkinson disease (PD) is the second most common neurodegenerative disorder. Its diagnosis relies solely on a clinical examination and is not straightforward because no diagnostic test exists. Large, population-based, prospective cohort studies designed to examine other outcomes that are more common than PD might provide cost-efficient alternatives for studying the disease. However, most cohort studies have not implemented rigorous systematic screening for PD. A majority of epidemiologic studies that utilize population-based prospective designs rely on secondary data sources to identify PD cases. Direct validation of these secondary sources against clinical diagnostic criteria is lacking. The Framingham Heart Study has prospectively screened and evaluated participants for PD based on clinical diagnostic criteria. We assessed the predictive value of secondary sources for PD identification relative to clinical diagnostic criteria in the Framingham Heart Study (2001-2012). We found positive predictive values of 1.0 (95% confidence interval: 0.868, 1.0), 1.0 (95% confidence interval: 0.839, 1.0), and 0.50 (95% confidence interval: 0.307, 0.694) for PD identified from self-report, use of antiparkinsonian medications, and Medicare claims, respectively. The negative predictive values were all higher than 0.99. Our results highlight the limitations of using only Medicare claims data and suggest that population-based cohorts may be utilized for the study of PD determined via self-report or medication inventories while preserving a high degree of confidence in the validity of PD case identification.

Prevalence of neurocognitive disorder in Huntington's disease using the Enroll-HD dataset.

Background: Cognitive decline in Huntington's disease (HD) begins early in the disease course, however the reported prevalence and severity of cognitive impairment varies based on diagnostic approach. A Movement Disorders Society Task Force recently endorsed the use of standardized DSM-5-based criteria to diagnose neurocognitive disorder (NCD) in Huntington's disease. Objectives: To determine the prevalence and severity of cognitive impairment across different stages of HD by applying NCD criteria (mild and major) to participant data from the Enroll-HD database. Methods: Enroll-HD participants were triaged into either premanifest (preHD), manifest or control groups. PreHD was further dichotomized into preHD near or preHD far based on predicted time to diagnosis using the scaled CAG-age product score (CAPs). Embedded cognitive performance and functional independence measures were used to determine prevalence of NCD (mild and major) for all groups. Results: Prevalence of NCD-mild was 25.2%-38.4% for manifest HD, 22.8%-47.3% for preHD near, 11.5%-25.1% for preHD far, and 8.8%-19.1% for controls. Prevalence of NCD-major was 21.1%-57.7% for manifest HD, 0.5%-16.3% for preHD near, 0.0%-4.5% for preHD far, and 0.0%-3.0% for controls. Conclusion: The prevalence of NCD in HD is elevated in preHD and demonstrates a sharp rise prior to diagnosis. In manifest HD, the vast majority of participants meet criteria for NCD. These findings are important for optimizing clinical care and/or anticipating the need for supportive services.

LASSI-L detects early cognitive changes in pre-motor manifest Huntington's disease: a replication and validation study.

Background and objectives: Cognitive decline is an important early sign in pre-motor manifest Huntington's disease (preHD) and is characterized by deficits across multiple domains including executive function, psychomotor processing speed, and memory retrieval. Prior work suggested that the Loewenstein-Acevedo Scale for Semantic Interference and Learning (LASSI-L)-a verbal learning task that simultaneously targets these domains - could capture early cognitive changes in preHD. The current study aimed to replicate, validate and further analyze the LASSI-L in preHD using larger datasets. Methods: LASSI-L was administered to 50 participants (25 preHD and 25 Healthy Controls) matched for age, education, and sex in a longitudinal study of disease progression and compared to performance on MMSE, Trail A & B, SCWT, SDMT, Semantic Fluency (Animals), and CVLT-II. Performance was then compared to a separate age-education matched-cohort of 25 preHD participants. Receiver operating curve (ROC) and practice effects (12 month interval) were investigated. Group comparisons were repeated using a preHD subgroup restricted to participants predicted to be far from diagnosis (Far subgroup), based on CAG-Age-Product scaled (CAPs) score. Construct validity was assessed through correlations with previously established measures of subcortical atrophy. Results: PreHD performance on all sections of the LASSI-L was significantly different from controls. The proactive semantic interference section (PSI) was sensitive (p = 0.0001, d = 1.548), similar across preHD datasets (p = 1.0), reliable on test-retest over 12 months (spearman rho = 0.88; p = <0.00001) and associated with an excellent area under ROC (AUROC) of 0.855. In the preHD Far subgroup comparison, PSI was the only cognitive assessment to survive FDR < 0.05 (p = 0.03). The number of intrusions on PSI was negatively correlated with caudate volume. Discussion: The LASSI-L is a sensitive, reliable, efficient tool for detecting cognitive decline in preHD. By using a unique verbal learning test paradigm that simultaneously targets executive function, processing speed and memory retrieval, the LASSI-L outperforms many other established tests and captures early signs of cognitive impairment. With further longitudinal validation, the LASSI-L could prove to be a useful biomarker for clinical research in preHD.

Comparison of enrollees and decliners of Parkinson disease sham surgery trials.

Concerns have been raised that persons with serious illnesses participating in high-risk research, such as PD patients in sham surgery trials, have unrealistic expectations and are vulnerable to exploitation. A comparison of enrollees and decliners of such research may provide insights about the adequacy of decision making by potential subjects. We compared 61 enrollees and 10 decliners of two phase II neurosurgical intervention (i.e., cellular and gene transfer) trials for PD regarding their demographic and clinical status, perceptions and attitudes regarding research risks, potential direct benefit, and societal benefit, and perspectives on the various potential reasons for and against participation. In addition to bivariate analyses, a logistic regression model examined variables regarding risks and benefits as predictors of participation status. Enrollees perceived lower risk of harm while tolerating higher risk of harm and were more action oriented, but did not have more advanced disease. Both groups rated hope for benefit as a strong reason to participate, whereas the fact that the study's purpose was not solely to benefit them was rated as "not a reason" against participation. Hope for benefit and altruism were rated higher than expectation of benefit as reasons in favor of participation for both groups. Enrollees and decliners are different in their views and attitudes toward risk. Although both are attracted to research because of hopes of personal benefit, this hope is clearly distinguishable from an expectation of benefit and does not imply a failure to understand the main purpose of research.

Ethics of sham surgery: perspective of patients.

Sham surgery is used as a control condition in neurosurgical clinical trials in Parkinson's disease (PD) but remains controversial. This study aimed to assess the perspective of patients with PD and the general public on the use of sham surgery controls. We surveyed consecutive patients from a university-based neurology outpatient clinic and a community-based general internal medicine practice. Background information was provided regarding PD and two possible methods of testing the efficacy of a novel gene transfer procedure, followed by questions that addressed participants' opinions related to the willingness to participate and permissibility of blinded and unblinded trial designs. Two hundred eighty-eight (57.6%) patients returned surveys. Patients with PD expressed less willingness to participate in the proposed gene transfer surgery trials. Unblinded studies received greater support, but a majority would still allow the use of sham surgery. Those in favor of sham surgery were more educated and more likely to use societal perspective rationales. Patients with PD are more cautious about surgical research participation than patients with non-PD. Their policy views were similar to others', with a majority supporting the use of sham controls. Future research needs to determine whether eliciting more considered judgments of laypersons would reveal different levels of support for sham surgery.

The challenges of residents teaching neurology.

BACKGROUND: Teaching is integrated into the daily practice of residents, and it is a skill necessary for practice as well as academics. The settings in which teaching and learning take place are ubiquitous but include classrooms, small groups, bedside rounds, and grand rounds. Given the learning environment of residency, neurology residents should have working knowledge of basic principles of effective teaching to make learning successful. Teaching also reinforces knowledge, and residents will likely be better practitioners if some basic skills of teaching are practiced. REVIEW SUMMARY: Neurology teaching techniques for residents are rarely addressed in the medical literature. Although information regarding teaching principles in medicine exists, there is little information regarding how residents teach. We examine and review some of the more effective methods and appreciated qualities in teachers, with a particular emphasis for the neurology resident. We also review whom neurologists need to teach and the various settings in which teaching may take place. CONCLUSIONS: Neurology residents encounter a variety of audiences in a variety of settings that require diverse teaching skills to effectively convey information to other providers as well as patients. The majority of these skills should be learned in residency to establish a foundation for teaching, regardless of future practice settings.

Temporal course of the tourette syndrome clinical triad.

BACKGROUND: Tourette syndrome (TS) is a disorder characterized by childhood onset of motor and phonic tics, often with improvement of tic symptoms by young adult years. The temporal course of tics and commonly comorbid behavioral symptoms is still not well characterized. METHODS: In order to clarify the time course of tics and comorbid attention deficit hyperactivity disorder (ADHD) or obsessive compulsive disorder (OCD) in TS, we administered a brief survey regarding the course of symptoms at a single point in time to 53 TS patients aged 13-31 years. RESULTS: Mean age (±SD) at symptom onset was 7.9 (±3.6) years for tics, 7.9 (±3.5) for ADHD, and 9.2 (±5.0) for OCD. Age at peak symptom severity was 12.3 (±4.6) years for tics, 10.8 (±3.8) for ADHD, and 12.6 (±5.5) for OCD. Tics, ADHD, and OCD were reported to be no longer present in 32.0%, 22.8%, and 21.0% of subjects, respectively. Decline in symptom severity began at age 14.7 (±3.7) years for tics, 13.9 (±2.9) for ADHD, and 15.1 (±5.0) for OCD. Remission of symptoms occurred at age 17.4 (±3.8) years for tics, 17.4 (±1.3) for ADHD, and 15.6 (±2.3) for OCD. DISCUSSION: Our data confirm and expand previously reported TS spectrum symptom milestones and may guide design of future research aimed at improving the course of TS.

Botulinum toxin for painful spasms from focal seizures: theoretical considerations and case report.

INTRODUCTION: Botulinum toxin (BTX) has been used to treat muscle overactivity and can reduce pain from muscle spasm. There are no previous reports to our knowledge of using BTX to treat the pain from intractable focal motor seizures. CASE REPORT: We present a case of chronic, focal, muscle pain, and spasm secondary to intractable focal motor seizures treated with BTX. The patient experienced significant relief in muscle pain despite continued seizures. CONCLUSIONS: On the basis of the case presented, BTX may have a limited role in the treatment of pain from muscle spasm in intractable focal seizures. Further study is necessary to see if this use of BTX is generally applicable.

Writing from the wards: advice for residents.

INTRODUCTION: Published articles share information and ideas across fields and can be a part of educational and career development. Academic and personal interests are the typical motivators, but many residents have trouble with the logistics of writing and the simple act of getting started. OBJECTIVE: The following article gives concrete advice, structural recommendations and addresses logistical concerns in writing manuscripts, focusing on case reports. METHODS: The process of writing a paper results in self-teaching, while striving to teach others. Working on case reports often produces posters and presentations on the way to writing the manuscript. This article reviews different types of case reports: from the classic sentinel case, to case series, and video submissions, to teaching cases. A "how to" strategy is presented in the writing process, from idea, to data, to writing itself. Aspects such as choosing your audience and journal are discussed, as well as employing coauthors and working together to produce a polished manuscript. CONCLUSIONS: Residents and fellows are immersed in clinical medicine but may not possess experience in writing journal articles. Presented is advice on and logistics of writing manuscripts that are based on clinical data and clinical experience. Through utilizing a structured approach and understanding the practicalities involved, more physicians in training can write from the wards.

The neurology resident as teacher: evaluating and improving our role.

There is a need to improve the quality of teaching done by neurology residents because neurology residents are intimately involved in medical student education. This article reviews the available literature on techniques to improve the teaching ability of resident physicians. Eight randomized prospective studies were identified from health and education databases. The outcomes measured were student ratings of residents or objective ratings of interactions between residents and students. The skills curriculum provided a more robust response, and the objective standardized teaching examination (OSTE) provided a standardized outcome. There continues to be a need for studies specifically addressing the teaching by neurology residents and fellows.